title: Characterization of statin dose response in electronic medical records.
abstract: Efforts to define the genetic architecture underlying variable statin response have met with limited success, possibly because previous studies were limited to effect based on a single dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 preselected variants. Two large biobanks were used to construct dose-response curves for 2,026 and 2,252 subjects on simvastatin and atorvastatin, respectively. Atorvastatin was more efficacious, was more potent, and demonstrated less interindividual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in subjects homozygous for the minor allele vs. 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand the genetic factors contributing to drug response.
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: W-Q
authors.initials: WQ
authors.lastname: Wei
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: L
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Waitara
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: O F
authors.initials: OF
authors.lastname: Iwuchukwu
authors.affiliation: 1] Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA [2] Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [3] Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [4] Office of Personalized Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Department of Biomedical Informatics, University of Texas, Houston, Texas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Biomedical Informatics, University of Texas, Houston, Texas, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Krauss
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, Califonia, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Kaiser Permanente Georgia, Center for Health Research Southeast, Atlanta, Georgia, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Davis
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Berg
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Peissig
authors.affiliation: Essentia Institute of Rural Health, Duluth, Minnesota, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Department of Internal Medicine, Sanford Healthcare, Fargo, North Dakota, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Wilke
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Denny
mesh_terms: D000465:Algorithms; D000483:Alleles; D000069059:Atorvastatin; D008078:Cholesterol, LDL / Q000097:blood; D015331:Cohort Studies; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D057286:Electronic Health Records; D005838:Genotype; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008055:Lipids / Q000097:blood; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin